Sudden cardiac death due to ventricular arrhythmias is a major public health problem, accounting for 10-20% of all deaths in adults in the US. Current predictors can identify patient subsets at high risk, but unfortunately sudden death is the first manifestation of heart disease in up to half the victims. Costly implantable defibrillators in high-risk patients are the only real therapeutic option at present. Conventional anti-arrhythmic drug therapy targeting membrane ion channels has either no survival benefit or even increases mortality. Thus, a key challenge in the arrhythmia field is to understand fundamental mechanisms in order to find better ways to predict and treat ventricular arrhythmias. Since the pharmaceutical industry has all but abandoned drug development for cardiac arrhythmia, in 2018 there are fewer antiarrhythmic agents available for clinical use than 20 years ago. Hence, another key challenge for academia is to improve the efficacy of existing antiarrhythmic drugs and find new compounds that could be developed therapeutically. The overall vision of my R35 research program is to better understand molecular and cellular mechanisms responsible for arrhythmia and to use this knowledge to improve the care of patients with arrhythmia disorders. To accomplish this vision, the proposed research program will build on our prior accomplishments (e.g, finding new treatments for catecholaminergic polymorphic ventricular tachycardia or developing human induced pluripotent stem cells as better tools for arrhythmia research) to pioneer discovery in three areas: (1) Discovery of new arrhythmia mechanisms; (2) Discovery of new antiarrhythmic treatments; and (3) Development of new approaches to individualize care of patients with arrhythmia disorders. Accomplishing these goals will provide major conceptual advances for our understanding of the pathophysiology and treatment of acquired and inherited arrhythmia syndromes.